Danon disease: a novel Lamp-2 gene mutation in a family with four affected members

This is a report of a family with four members affected with Danon disease and variable clinical presentations, including cardiomyopathy, skeletal muscle pathology, and hepatopathy. Analysis by electron microscopy of the quadriceps muscle from the proband and his brother showed abnormal mitochondria, and immunohistochemistry revealed no expression of LAMP-2 protein. This defect is due to a yet undescribed mutation located at the second nucleotide in the intron 8 of the Lamp-2 gene (c.1093+2 T>A) that generated exon 8 skipping confirmed at RNA level in the proband.     

A case of vogt-koyanagi-harada syndrome in a patient affected by hodgkin's disease

Summary The Vogt-Koyanagi-Harada (VKH) syndrome, a disease of unknown origin, characterized by inflammation of the uveal tract, retina and meninges, was observed in a patient with Hodgkin's disease (HD) who had been treated with chemotherapy and radiotherapy. Ten years later the patient developed a cluster of neurological symptoms and signs (fever, pain, bilateral hypoacousia, dizziness, uveitis and psychiatric disorder) which were initially interpreted as a relapse of HD. The diagnosis of VKH syndrome was thereafter suspected from the clinical findings, response to therapy and further evolution. During the follow-up (14 months) the patient showed a varying course; hypoacousia remained unaltered while uveitis recurred and only a partial improvement was obtained by immunosuppressive therapy.     

Clinicopathological features of genetically confirmed Danon disease

BACKGROUND: Danon disease is due to primary deficiency of lysosome-associated membrane protein-2. OBJECTIVE: To define the clinicopathologic features of Danon disease. METHODS: The features of 20 affected men and 18 affected women in 13 families with genetically confirmed Danon disease were reviewed. RESULTS: All patients had cardiomyopathy, 18 of 20 male patients (90%) and 6 of 18 female patients (33%) had skeletal myopathy, and 14 of 20 male patients (70%) and one of 18 female patients (6%) had mental retardation. Men were affected before age 20 years whereas most affected women developed cardiomyopathy in adulthood. Muscle histology revealed basophilic vacuoles that contain acid phosphatase-positive material within membranes that lack lysosome-associated membrane protein-2. Heart transplantation is the most effective treatment for the otherwise lethal cardiomyopathy. CONCLUSIONS: Danon disease is an X-linked dominant multisystem disorder affecting predominantly cardiac and skeletal muscles.     

Danon disease: Further clinical and molecular heterogeneity

Two families of Greek patients with subclinical to severe cardiomyopathy are presented. The diagnosis of Danon disease was supported by a total lack of LAMP2 immunostaining in cultured skin fibroblasts and muscle biopsies. The LAMP2 mutation carried by one patient (c.928G>A) has already been reported but with different symptoms. The second patient had a novel point deletion. This has not been described previously, but it could be detected easily by restriction analysis. This mutation was also found in the patient's brother, and it was associated with severe cardiomyopathy leading to heart failure. Surprisingly, the proband also had partial reduction of α‐galactosidase A activity, despite the absence of characteristic clinical features of Fabry disease. A substitution in the GLA gene (c.937G>T) was found, and its involvement in the cardiac disease is discussed. Muscle Nerve, 2009     

Meningiomas in a male fetus from a hormonally dysequilibrated mother

Congenital multiple meningiomas in a male fetus of 37 cm length are reported. The tumor was histologically a highly vascular meningioma. An unbalanced level of hormones before and at the beginning of the mother's pregnancy could be ascertained, which resulted in gestational abnormality.     

Neuropsychological functioning following cardiac transplant in Danon disease

Purpose: To present a unique case involving a 31-year-old male with Danon disease (diagnosed at 14) who received cardiac transplant and subsequent cardiac re-transplant. Research design: Brief report/case study. Methods: Serial neuropsychological assessment across a 23-year span along with a review of school records and prior psychoeducational assessment. Results: A consistent pattern of higher level cognitive impairment from childhood through adulthood was found. This pattern is interpreted in light of the sparse literature regarding cognitive and adaptive functioning related to Danon disease. Conclusions: The noteworthy aspects of this case include the preservation of some academic abilities and an unexpected level of functional independence given cognitive concerns. This case study further explores the nature of the deficits related to Danon disease and highlights the benefits of neuropsychological evaluation to guide functional interventions and maximize level of independence across the life span.     

Danon disease: an unusual presentation of autism

Danon disease is an X-linked cardioskeletal myopathy, originally reported as "lysosomal glycogen storage disease with normal acid maltase," resulting from a primary deficiency of lysosome-associated membrane protein-2 because of mutations in the lysosome-associated membrane protein-2 gene. Classic clinical features in males include cardiomyopathy (100%, eventually), myopathy (90%), and mental retardation (70%), but mostly of a mild degree. We report on an unusual presentation in a patient with autism, motor delay, and a normal cardiac evaluation. The presence of multiorgan involvement, including elevated liver enzymes, abnormal cranial magnetic resonance imaging, and diffuse hypotonia with swallowing difficulties, prompted a muscle biopsy. A quadriceps muscle biopsy was performed, and the findings were most suspicious for a glycogen storage-type disease. Subsequently, a pathogenic lysosome-associated membrane protein-2 mutation was found. To our knowledge, there are no previous clinical reports of autism in children with Danon disease.     

Abnormal chaperone-mediated autophagy (CMA) in cardiomyocytes of a boy with Danon disease

Ultrastructural analysis of the cardiomyocyte structure in Danon disease reveals dramatic accumulation of abnormal late autophagic vacuoles (AVd) suggestive of primary lysosomal defect. Moreover, the accumulation of AVd in cardiomyocytes is consistent with a decreased rate of autophagic to lysosomal trafficking. These results suggest that the loss of the LAMP-2 protein strongly inhibits uptake of proteins into lysosomes for degeneration. The significant reduction of chaperone-mediated autophagy (CMA) activity in the affected cardiomyocytes induces a dramatic increase in the number and size of AVd and a severe reduction of myocardial contractility.     

Mild form of Danon disease: two case reports

Danon disease is typically lethal by the mid-twenties in male patients due to cardiomyopathy. This report aims to describe two unrelated male patients showing mild manifestations of the disease. A 39-year-old man presented with a 10-year history of elevated serum creatine kinase levels with slowly progressive muscle weakness. Muscle pathology showed autophagic vacuoles with sarcolemmal features. Genetic testing revealed a hemizygous mutation in exon 9b, an alternatively spliced exon, of lysosome-associated membrane protein-2 (LAMP-2) (c.1097_1098delAA). Cardiac testing showed asymptomatic mild left ventricular hypertrophy. He had borderline intelligence. Early stage of retinopathy was detected. Another male patient, currently 53-year-old, had asymptomatic supraventricular extrasystole and muscle weakness but no intellectual disability, harboring the same mutation. He also had retinopathy. The present patients commonly carry a mutation in exon 9b of LAMP-2, suggesting that mutations in the exon are associated with a mild form of Danon disease.     

Danon disease due to a novel splice mutation in the LAMP2 gene

Danon disease is a rare X-linked dominant disorder caused by lysosomal-associated membrane protein 2 (LAMP2) deficiency and is characterized by hypertrophic cardiomyopathy, cardiac conduction abnormalities, skeletal vacuolar myopathy, variable degree of mental retardation, and peripheral pigmentary retinopathy. We describe a novel splice mutation in the LAMP2 gene in a French Canadian family. By identifying this novel mutation we were able to offer genetic screening and counseling to all family members. Presymptomatic diagnosis is important as cardiac surveillance can be life-saving.